Sepsis syndrome is a serious whole-body inflammation disease caused by bacteria-released toxins into blood. This syndrome often causes blood coagulation of the patients, and they finally die of multiple organ dysfunction syndromes. According to several epidemiological studies, rates of hospitalization for severe sepsis range from 50 to 300 cases per 100,000 in USA, and the mortality of severe sepsis in ICU ranges from 18% to 55%. The medical cost per patient was estimated from US$26,450 to US$39,100.
In Taiwan, the rate of severe sepsis incidence is 359 per 100,000, and the mortality of severe sepsis is about 30%. The estimated cost for caring a sepsis patient is 866-6505 USD. So far, the main management of sepsis is symptoms relief and vital signs supports, such as using anti-inflammation drugs, antibiotics, blood-vessel constriction drugs and intravenous drips.
Currently, the only one FDA-proved therapeutic agent for reducing mortality of severe sepsis patients and treating sepsis is Drotrecogin alfa (Xigris®). Xigris® is a recombinant human activated protein C by recombinant genetic technology. The recombinant human activated protein C could inhibit the activity of the Factor Va and Factor VIIIa, inhibit the synthesis of the thrombin and inhibit the synthesis of plasminogen activator inhibitor-1 (PAI-1) to regulate the coagulation reaction and possess the features of anti-thrombus and fibrinolysis. However, according to several clinical researches, the benefit effects of Xigris® on reducing mortality of servere sepsis patients is still controversial, so new therapeutic agents for sepsis is still desired.
Serotonin (also called 5-hydroxytryptamine or 5-HT) is a neurotransmitter which could induce coagulation of platelets, contraction of coronary artery. 5-HT2A receptor, which is one subtype of the 5-HT receptor family and a G-protein coupled receptor.
The present 5-HT2A receptor antagonists include sarpogrelate and ketanserin. The method of treatment sepsis using 5-HT2A receptor antagonists is still under research. In order to overcome the drawbacks in the prior art, a novel series of 8-phenylisoquinolines and pharmaceutical composition used in treatment for sepsis is provided.